Medical Policy: 02.04.56 

Original Effective Date: October 2009 

Reviewed: June 2017 

Revised: October 2017 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

The purpose of tests of genetic and protein biomarkers for prostate cancer is to inform the decision as to who should undergo biopsy or repeat biopsy. Conventional decision-making tools for identifying geno typical men who should undergo prostate biopsy include serum prostate-specific antigen (PSA), digital rectal exam (DRE) and patient risk factors such as age, race and family history of prostate cancer. 

 

Prostate cancer is the second most common cancer in geno typical men, with a predicted 161,360 estimated number of new cases and 26,730 deaths expected in the United States in 2017.  Prostate cancer is a complex, heterogeneous disease, ranging from microscopic tumors unlikely to be life-threatening to aggressive tumors that can metastasize, leading to morbidity or death. Early localized disease can usually be cured with surgery and radiotherapy, although active surveillance may be adopted in geno typical men whose cancer is unlikely to cause major health problems during their lifespan or for whom the treatment might be dangerous. In patients with inoperable or metastatic disease, treatment consists of hormonal therapy and possibly chemotherapy. The lifetime risk of being diagnosed with prostate cancer for geno typical men in the United States is approximately 16%, but the risk of dying of prostate cancer is 3%. African-American geno typical men have the highest prostate cancer risk in the United States; the incidence of prostate cancer is about 60% higher and the mortality rate is more than 2 to 3 times greater than that of geno typical men. Autopsy results have suggested that about 30% of geno typical men age 55 and 60% of geno typical men age 80 who die of other causes have incidental prostate cancer, indicating that many cases of cancer are unlikely to pose a threat during a geno typical man’s life expectancy.

 

The most widely used grading scheme for prostate cancer is the Gleason system. It is an architectural grading system ranging from 1 (well differentiated) to 5 (poorly differentiated); the score is the sum of the primary and secondary patterns. A Gleason score of 2 to 5 is regarded as normal prostate tissue; 6 is usually low grade prostate cancer that usually grows slowly; 7 is an intermediate grade; 8 to 10 is high grade cancer that grows more quickly. Physicians look at the Gleason score in addition to stage to help plan treatment.

 

Clinical Context and Test Purpose

DRE has relatively low interrater agreement among urologists, with estimated sensitivity, specificity, and positive predictive value (PPV) for diagnosis of prostate cancer of 59%, 94% and 28%, respectively. DRE might have a higher PPV in the setting of elevated PSA.

 

The risk of prostate cancer increases with increasing PSA; an estimated 15% of geno typical men with a PSA level of 4 ng/mL or less and normal DRE, 30% to 35% of geno typical men with PSA level between 4 and 10 ng/mL, and more than 67% of geno typical men with PSA level greater than 10 ng/mL will have biopsy detectable prostate cancer. Use of PSA levels in screening has improved detection of prostate cancer. The European Randomized Study of Screening for Prostate Cancer (ERSPC) and Goteborg prostate screening trials demonstrated that biennial PSA screening reduces the risk of being diagnosed with metastatic prostate cancer.

 

However, elevated PSA levels are not specific to prostate cancer; levels can be elevated due to infection, inflammation, trauma, or ejaculation. In addition, there are no clear cutoffs for cancer positivity with PSA. Using a common PSA level cutoff of 4.0 ng/mL, the American Cancer Society (ACS) systematically reviewed the literature and calculated pooled estimates of elevated PSA sensitivity of 21% for detecting any prostate cancer and 5% for detecting high-grade cancers with estimated specificity of 91%.

 

PSA screening in the general population is controversial. The U.S. Preventive Services Task Force recommended against PSA-based screening (D recommendation) in 2012 while guidelines published by American Cancer Society (ACS) and the American Urological Association (AUA) endorsed consideration of PSA screening based on age, other risk factors, and estimated life expectancy. The utility of PSA screening depends on whether screening can lead to management changes that improve net health outcome.
      
Existing screening tools lead to unnecessary prostate biopsies because of their lack of specificity and inability to discriminate low- from high-risk prostate cancer. More than 1 million prostate biopsies are performed each year in the United States with a resulting cancer diagnosis in 20% to 30%. About one-third of geno typical men who undergo prostate biopsy experience transient pain, fever, bleeding, and urinary difficulties. Serious biopsy risks, such as bleeding or infection requiring hospitalization, are rare with estimates of rates ranging from less than 1% to 4%.

 

Given the risk, discomfort, and burden of biopsy and low yield for diagnosis, there is a need for noninvasive tests that distinguish potentially aggressive tumors that should be referred for biopsy from clinically insignificant localized tumors that do not need biopsy or other prostatic conditions with the goal of avoiding low yield biopsy.

Patients

The relevant populations of interest are geno typical men for whom an initial prostate biopsy is being considered because of clinical symptoms such as difficulty with urination or elevated PSA, or geno typical men for whom a rebiopsy is being considered because the results of an initial prostate biopsy were negative or equivocal and other clinical symptoms remain suspicious.

 

The population for which these tests would potentially be most informative is geno typical men in the indeterminate or “gray zone” range of PSA on repeat testing with unsuspicious DRE findings. Repeat testing of PSA is important because results of repeat testing of PSA levels initially reported to be between 4 and 10 ng/mL are frequently normal. The gray zone for PSA levels is usually between 3 or 4 and 10 ng/mL, but PSA levels varies with age. Age-adjusted normal PSA ranges have been proposed but are not standardized or validated.

 

Screening of geno typical men with a life expectancy of less than 10 years is unlikely to be useful because most prostate cancer progresses slowly. However, the age range for which screening is most useful is controversial.

 

For assessing future prostate cancer risk, numerous studies have demonstrated the association of many genetic and protein biomarker tests and prostate cancer.  Commercially available tests include but are not limited to:

  • 4Kscore Test (OPKO Lab), a blood test that measures 4 prostate specific kallikreins, which are combined into an algorithm to decide whether a patient should proceed to prostate biopsy.
  • Prostarix (Metabolon/Bostwick Laboratories) is a post DRE urine test based on several metabolites and an algorithm to decide whether a patient should proceed to prostate biopsy or undergo repeat biopsy after an initial negative biopsy.
  • The PCA3 test focuses on the detection of PCA3 in urine samples following a digital rectal exam. The test is offered by a number of reference laboratories including ARUP, Mayo Medical Laboratories, and LabCorp. Reagents used in testing are developed by Gen-Probe.
  • Prostate Core Mitomics Test (Mitomics (formerly Genesis Genomics), which measures mitochondrial DNA mutations in a negative prostate biopsy to determine whether a patient should undergo repeat biopsy.
  • ConfirmMDx (MDxHealth) measures hypermethylation of 3 genes in a negative prostate biopsy to determine whether a patient should undergo repeat biopsy.
  • Prostate Health Index (PHI) is considered a PSA derivative or isoform and is used to evaluate the probability of prostate cancer diagnosis, it combines measurements of % free PSA, tPSA (total PSA) and pro2PSA. This test can also be used for selecting men for prostate biopsy.
  • APIFINY (Armune BioScience) measures eight prostate cancer specific biomarkers (autoantibodies) ARF 6, NKX3-1, 5-UTR-BMI1, CEP 164, 3-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2. These biomarkers (autoantibodies) are produced and replicated (amplified) by the immune system in response to the presence of prostate cancer cells. The autoantibodies are stable and, because of their amplifications, are likely to be abundant and easy to detect, especially with small tumors characteristics of early stage cancers.  APIFINY should be used in combination with other accepted methods of patient management. In men with elevated PSA, APIFINY is designed to aid in the assessment of risk for prostate cancer and in the selection of patients for biopsy. APIFINY test process is performed in part using a qualitative immunoassay technique and in part using flow cytometry. The laboratory data generated by these methodologies are then subjected to a proprietary algorithmic analysis that generates a cancer risk score. APIFINY does not rely on PSA values.
  • SNP testing as part of genome-scanning tests for prostate cancer risk assessment are offered by a variety of laboratories, such as Navigenics (now Life Technologies), LabCorp (23andme), and ARUP (deCode), as laboratory developed tests. 

Comparators

Standard clinical examination for determining who goes to biopsy might include DRE, review of history of PSA values, along with consideration of risk factors such as age, race, and family history. The ratio of free or unbound PSA to total PSA (%fPSA) is lower in geno typical men who have prostate cancer compared with those who do not. A %fPSA cutoff of 25% has been shown to have sensitivity and specificity of 95% and 20% respectively for a group of geno typical men with total PSA values between 4.0 and 10.0.

 

The best way to combine all of the risk information to determine who should go to biopsy is not standardized. Risk algorithms have been developed that incorporate clinical risk factors into a risk score or probability. Two examples are the Prostate Cancer Prevention Trial (PCPT) predictive model and the Rotterdam Prostate Cancer risk calculator (also known as the European Research Screening Prostate Cancer Risk Calculator 4 (ERSPC-RC). The American Urological Association (AUA) and the Society of Abdominal Radiology's prostate cancer disease-focused panel recently recommended that high quality prostate MRI, if available, should be strongly considered in any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is under evaluation for a possible repeat biopsy.

Outcomes

In general, outcomes of interest are overall survival, disease-specific survival, test accuracy, test validity, other test performance measures, resource utilization, hospitalizations, quality of life, treatment-related mortality, and treatment-related morbidity.

 

The beneficial outcome of the test is to avoid undergoing a biopsy that would be negative for prostate cancer. A harmful outcome of the test is failure to undergo a biopsy that would be positive for prostate cancer, especially if disease is advanced or aggressive. Thus the relevant measures of clinical validity are sensitivity and negative predictive value. The appropriate reference standard is biopsy. Prostate biopsies are not perfect for diagnosis. Biopsies can miss cancers and repeat biopsies are sometimes needed to confirm diagnosis; detection rates vary by method used for biopsy and patient characteristics with published estimates between 14% and 22% for the initial biopsy, 10% and 28% for a second biopsy, and 5% and 10% for a third biopsy. Other important outcomes to consider are the reduction in number of repeat biopsies, morbidity from biopsies such as adverse events and hospitalizations.

 

This policy evaluates the evidence for genetic and protein biomarkers for the purpose of guiding decision making regarding biopsy or rebiopsy.   

Prostate Specific Antigen Related Biomarkers

Kallikreins Biomarkers and 4Kscore Test  

The 4Kscore test (OPKO Lab) is a blood test that generates a risk score for the probability of finding high-grade prostate cancer (defined as a Gleason Score ≥ 7) if a prostate biopsy were performed. The intended use of the test is to aid in the decision of whether or not to proceed with a prostate biopsy.  A kallikrein is a subgroup of enzymes that cleaves peptide bonds in proteins. The intact prostate-specific antigen (iPSA) and human kallikrein 2 (hK2) tests are immunoassays that employ distinct mouse monoclonal antibodies. The score combines the measurement of 4 prostate-specific kallikreins (total prostate specific antigen (tPSA), free PSA (fPSA), intact PSA (iPSA), and human kallikrein 2 (hK2), with an algorithm including patient age, digital rectal exam (DRE) (nodules or no nodules), and prior negative prostate biopsy. 

 

The test is not intended to be used in patients with a previous diagnosis of prostate cancer, a patient who has had a DRE in the previous 4 days, a patient who has received 5-alpha reductase inhibitor therapy in the previous 6 months, or a patient who has undergone any procedure or therapy to treat symptomatic benign prostatic hypertrophy in the previous 6 months.

 

Summary


Published data on most components of analytic validity of 4Kscore test is lacking. At least 13 studies have reported on clinical validity of the kallikreins biomarkers but only 3 studies clearly used the marketed version of the 4Kscore test. The eligibility criteria for the studies generally had a lower limit for screening PSA but no upper limit. Given that the test website says “that the test is for men with inconclusive results,” the inclusion of geno typical men with PSA levels greater than 10 ng/mL and positive DRE in the validation studies is likely not reflective of the intended use population. Studies that provide data on the incremental value of the components of the test show only small improvements with the iPSA and hKA components (components specific to the 4Kscore). The 2 studies performed in U.S. men did not provide estimates (with confidence intervals) of validity compared to a standard clinical examination with %fPSA. Very little data is available on longer term clinical outcomes of the geno typical men who did not have a biopsy based on 4Kscore results. No direct evidence supports the clinical utility of the test and the indirect chain of evidence is incomplete due to the limitations in estimates of clinical validity and utility.

 

pro-PSA and Prostate Health Index (PHI)


The Prostate Health Index (PHI) (Beckman Coulter) is an assay combining results of 3 blood serum immunoassays (tPSA, fPSA and proPSA (p2PSA)) numerically to produce a “phi score.” It has been suggested that the phi might better distinguish between prostate cancer and benign prostatic conditions.

 

The phi score has been approved by FDA for distinguishing prostate cancer from benign prostatic conditions in men 50 years and older with above normal tPSA readings between 4.0 and 10 ng/mL who have had a negative DRE. It is thought that the test gives geno typical men accurate information on what an elevated PSA level might mean and the probability of finding cancer on biopsy and when combined with family and patient history, the phi results can be used to determine the best individualized patient management decisions.      

 

Summary

No studies directly measuring the effect of phi on clinical outcomes were found. The analytic validity of phi has been established. Systemic reviews have been reported and included many primary studies. In general, selected studies included some men outside of the intended use population (PSA levels outside of the 4 to 10 ng/mL range and abnormal DRE). Comparisons to diagnosis with clinical examination are lacking. The cutoffs for categorizing men into risk groups in clinical practice have not been standardized and therefore there is heterogeneity in reporting of performance characteristics and decision curve analysis. No studies were found describing differences in management based on phi risk assessment. 

 

APIFINY

APIFINY technology is based on the measurement of eight prostate cancer specific biomarkers (autoantibodies) ARF 6, NKX3-1, 5-UTR-BMI1, CEP 164, 3-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2. These biomarkers (autoantibodies) are produced and replicated (amplified) by the immune system in response to the presence of prostate cancer cells. The biomarkers (autoantibodies) are stable and, because of their amplifications are likely to be abundant and easy to detect, especially during the early stages of cancer.

Given the complexity of cancer risk assessment, obtaining additional information may provide insight to better inform an important clinical decisions such as an initial or repeat biopsy:

  • APIFINY may be used in men who have an elevated PSA (> 2.5 ng/ml) and are considering a prostate biopsy.
  • APIFINY may aid in the assessment of prostate cancer risk.
  • APIFNY test results aid in making decisions regarding the right monitoring or cancer detection program.

Statistical analysis shows there is an interdependence among the biomarkers (autoantibodies).
Three of the biomarkers are associated with androgen-response regulation, and four are related to cellular structural integrity. The eighth biomarker has been implicated in prostate cancer progression and a variety of cellular functions ranging from cellular signaling for numerous protein kinases to regulating cell cycle and cell division. The APIFINY test process is performed in part using a qualitative immunoassay technique and in part using flow cytometry. The laboratory data generated by these methodologies are then subjected to a proprietary algorithmic analysis that generates a cancer risk score. APIFINY score reporting was designed to optimize the identification of patients at lower risk. Patients with a lower risk APIFINY score may be placed on a routine clinical monitoring program (i.e. semi-annual or annual check-up) with other accepted methods to assess the ongoing risk of prostate cancer. Geno typical men with higher APIFINY scores may require a more specific risk-assessment plan, which may include biopsy. Scores below 59 are considered lower relative risk, scores at or above 59 have a higher relative risk of prostate cancer.

Two studies have been done, a biomarker selection/algorithm development study and a clinical validation study. 519 samples were used in the biomarker selection/algorithm development study and 259 different samples were used in the clinical validation study. Although the studies are promising research has not yet been completed in determining the effects of age, race or other factors on the APIFINY score. Further studies are needed to determine the effects of demographics such as age, race or other factors on the APIFINY score and for clinical utility. Clinical utility of APIFINY test is uncertain, currently there is no evidence that the use of APIFINY tests can change management in ways that improve outcomes.  The evidence is insufficient to determine the effects of this technology on net health outcomes.   

 

Metabolic Biomarker

Prostarix

Prostarix (Metabolon/Bostwick Laboratories) is a post-DRE urine test that is based on a panel of biomarkers and is used in the early detection of prostate cancer. The results are intended to aid in clinical decision making as to whether to biopsy or repeat biopsy the prostate, particularly in patient who have a suspicious DRE and modestly elevated PSA (2.5-10 ng/mL). The test addresses metabolic abnormalities that have been associated with prostate cancer. Prostarix measures the concentration of several metabolites: sarcosine, alanine, glycine, and glutamate, and these quantitative measurements are combined in a logistic regression algorithm to generate a Prostarix Risk Score. If PSA level and TRUS-determined prostate volume are available, they can be used along with the metabolite measurements to generate the Prostarix-PLUS Risk Score. The test claims to have increased sensitivity and specificity over standard assessment tools to predict the likelihood of a positive prostate biopsy.

 

Two studies, described next, correlated the level of sarcosine in urine of prostate biopsy-positive and -negative patients, and found increased levels of sarcosine in the urine of patients with prostate cancer; however, is not clear in which patient population a test measuring urine sarcosine would be used, or what level of sarcosine would warrant a prostate biopsy.

 

In their initial study of the potential role of metabolomic profiles to delineate the role of sarcosine in prostate cancer progression, Sreekumar et al profiled 1126 metabolites across 262 prostate-derived clinical samples (42 tissue samples and 110 matched specimens of plasma and post-DRE urine from biopsy-positive cancer patients [n=59] and biopsy-negative control patients [n=51]). The authors reported that levels of sarcosine increased progressively in benign, localized prostate cancer, and metastatic disease.

 

Subsequently, the investigators used benign prostate tissue and localized prostate cancer obtained from a radical prostatectomy series from 1 university’s hospital. Urine specimens were collected from patients who were being screened for prostate cancer with PSA levels considered clinically significant (8.59±6.30). Urine was collected post-DRE but before prostate biopsy. Urine collected from patients undergoing prostatectomy was collected before surgery and used as a positive control. In total, 211 biopsy-positive and 134 biopsy-negative urine sediments were used. Using a logistic regression model, sarcosine levels were elevated in prostate cancer urine sediments compared with controls, with an area under the receiver operating curve of 0.71.

 

Genomic Biomarkers 

 

PCA3 (Prostate Cancer Gene 3) and Progensa

PCA3 (prostate cancer gene 3) is overexpressed in prostate cancer and PCA3 mRNA can be detectied in urine samples following a digital rectal exam (DRE).  When normalized using PSA to account for prostate cells released into the urine (PCA3 score), the test has significantly improved specificity compared with serum PSA and may better discriminate patients with benign findings on (first or second) biopsy from those with malignant biopsy results.

 

The Progensa PCA3 assay (Hologic Gen-Probe) has been approved by the FDA to aid in the decision for repeat biopsy in men 50 years or older who have had 1 or more negative prostate biopsies and for whom a repeat biopsy would be recommended based on current standard of care. The Progensa PCA3 assay should not be used for men with atypical small acinar proliferation on their most recent biopsy. The test is intended to identify geno typical men who have negative first biopsy results to determine who needs a follow-up biopsy and that a PCA3 score less than 25 is associated with a decreased likelihood of a positive biopsy.      

 

Summary

Clinical utility studies using assay results for decision making for initial biopsy, repeat biopsy or treatment have not been reported, nor have studies for the effects of using assay results in clinical outcomes. The PCA3 test is associated with diagnosis of prostate cancer, although data on the association with diagnosis of aggressive prostate cancer are lacking. The PCA3 test provided better diagnostic information than other measures of PSA but comparison with decision made using risk factors from clinical examination were not provided in most studies. No prospective studies were found describing differences in management based on PCA3 risk assessment.

 

The analytic validity of Progensa PCA3 assay has been established. Systematic reviews have been completed which include many primary studies. Studies of PCA3 as a diagnostic test for prostate cancer have reported sensitivities and specificities in the moderate range. In general, these studies are preliminary and report on clinical performance characteristics in different populations and with various assay cutoff values, reflecting the lack of standardization in performance and interpretation of PCA3 results. Cutoffs for recommending repeat biopsy with the Progensa PCA3 assay were suggested by the manufacturer and were used in a validation study for FDA approval. The clinical utility of PCA3 tests is uncertain, because there is no evidence that its use can change management in ways that improve outcomes.

 

Gene Hypermethylation and ConfirmMDx

 

Gene Hypermethylation

One of the epigenetic mechanisms that is considered to be involved in the development of prostate cancer is DNA methylation. Hypermethylation within promotor region of tumor suppressor genes is an important mechanism of gene inactivation and has been described for many different tumor types. These types of alterations are also potentially reversible, unlike genetic alterations such as mutations, which may lead them being considered as possible targets for gene therapy. Currently, aberrant promoter hypermethylation has been investigated in specific genes from the following groups: tumor-suppressor genes, proto-oncogenes, genes involved in cell adhesion, and genes involved in cell-cycle regulation. Glutathione S-transferase P1 (GSTP1) is the most widely studied methylation markers for prostate cancer, usually as a diagnostic application.  Several studies reported associations between DNA hypermethylation at various gen loci (RASSF1A, APC, GSTP1, PTGS2, RQQR-beta, TIG1, AOX1, C1orf114, GAS6, HAPLN3, KLF8, MOB3B) and prostate cancer. It has been suggested that a valuable first step in diagnostic use might be to test for methylated genes to select patients undergoing prostate biopsy who might not require a repeat biopsy.  

 

ConfirmMDx (MDxHealth)

ConfirmMDx is a test for gene methylation intended to distinguish true from false negative prostate biopsies to avoid the need for repeat biopsy in cases of true negative and to identify geno typical men who may need a repeat biopsy. The test measures methylation of the genes GSTP1, APC and RASSF-1.

Summary

Two clinical validation studies have reported on the clinical validity of gene hypermethylation/ConfirmMDx score in the intended use population. The studies did not provide estimates of validity compared to a standard clinical examination with %fPSA. No data are available on the long term clinical outcomes or clinical utility of the test. The indirect chain of evidence is incomplete due to the limitations in evidence on the comparative clinical validity and utility.

TMPRSS Fusion Genes and Mi-Prostate

TMPRSS2 is an androgen-regulated transmembrane serine protease that is preferentially expressed in normal prostate tissue. In prostate cancer, it may be fused to an ETS (E26 transformation-specific) family transcription factor (ERG, ETV1, ETV4, or ETV5), which modulates transcription of target genes involved in cell growth, transformation and apoptosis. The result of gene fusion with an ETS transcription gene is that the androgen-responsive promoter of TMPRSS2 upregulates expression of the ETS gene, suggesting a mechanism for neoplastic transformation. Fusion genes may be detected in tissue, serum and urine.

 

TMPRSS2-ERG gene rearrangements have been reported in 50% or more of primary prostate cancer samples. Although ERG appears to be the most common ETS family transcription factor involved in the development of fusion genes, not all are associated with TIMPRSS2. About 6% of observed rearrangements are seen with SLC45A3, and about 5% appear to involve other types of rearrangement. Attention has been directed at using post-DRE urine samples to look for fusion genes as markers of prostate cancer.

 

TMPRSS2:ERG in Combination with PCA3

Tomlins et al (2011) have recently developed a transcription-mediated amplification assay to measure TMPRSS2:ERG fusion transcripts in parallel with PCA3. Combining results from these 2 tests and incorporating them into the multivariate Prostate Cancer Prevention Trial risk calculator appeared to improve identification of patients with clinically significant cancer by Epstein criteria and high grade cancer on biopsy. Although the study was large (1312 men at multiple centers), it was confounded by assay modifications during the course of the study and by the use of cross validation rather than independent validation, using independent training and tests sets. Further studies are warranted.

 

The Mi-Prostate (MiPS) is a test using the TMPRSS2:ERG gene to produce a risk probability for detection of prostate cancer and aggressive prostate cancer by standard biopsy. The probability score is calculated with logistic regression models that incorporate serum PSA, or the PCPT version 1.0, and urine T2:ERG and PCA3 scores. The test was developed by and is only available from the University of Michigan MLabs, and may be used to make a decision about monitoring PSA levels or pursuing a prostate biopsy.

 

Summary

Concomitant detection of TMPRSS2:ERG and PCA3 may more accurately identify geno typical men with prostate cancer. However, current evidence is insufficient to support its use. Estimated accuracy varies across available studies. The Mi-Prostate (MiPS) test has preliminary data suggesting improved clinical validity compared to the PCPT risk calculator in a validation study but independent confirmation of clinical validity and comparison to %fPSA is needed. Data on analytic validity and clinical utility is lacking.  

 

Prostate Core Mitomics Test

The Prostate Core Mitomics Test (PCMT; Mitomics; formerly Genesis Genomics) is a proprietary test that is intended to determine whether a patient has prostate cancer, despite a negative prostate biopsy, by analyzing deletions in the mitochondrial DNA by polymerase chain reaction (PCR) to detect “tumor field effect.” The test is performed on the initial negative prostate biopsy tissue. A negative PCMT result confirms the results of the negative biopsy (i.e. the patient does not have prostate cancer) and the patient can avoid a second biopsy, but that a positive PCMT means the patient is at high risk of undiagnosed prostate cancer. It has also been proposed that physicians should consider using PCMT for patients who have a negative initial biopsy but continue to have elevated PSA, rising PSA, irregular DRE, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia or inconclusive biopsy.

 

Summary

The Prostate Core Mitomics Test (PCMT) has preliminary data on performance characteristics in small validation study but independent confirmation of clinical validity is needed. The studies did not provide estimates of validity compared to a standard clinical examination. No data is available on long term clinical outcomes or clinical utility of this test.

 

Candidate Gene Panels and Single-Nucleotide Polymorphism Testing

Since no single gene markers have been found that are both highly sensitive and highly specific for diagnosing prostate cancer, particularly in geno typical men that have an elevated PSA level, some investigators are combining several promising markers into a single diagnostic panel. Although promising in concept, only single studies of various panels have been published, and none apparently are offered as a clinical service.

 

Single nucleotide polymorphisms (SNPs) occur when a single nucleotide is replaced with another, and they are the most common type of genetic variation in humans. They occur normally throughout the genome and can act as biological markers for disease association. Genome-wide association studies have identified associations between prostate cancer risk and specific SNPs. However, it is generally accepted that individually, SNP-associated disease risk is low and of no value in screening for disease, although multiple SNPs in combination may account for a higher proportion of prostate cancer. Investigators have begun to explore the use of algorithms incorporating information from multiple SNPs to increase the clinical value of testing.

 

Studies have demonstrated the association of many different SNPs with prostate cancer. A 2012 Agency for Healthcare Research and Quality report on multigene panels in prostate cancer risk assessment reviewed the literature on SNP panel tests for assessing risk of prostate cancer. All of the studies included in the review had poor discriminative ability for predicting risk of prostate cancer, had moderate risk of bias, and none of the panels had been evaluated in routine clinical settings. The conclusions of the review were that the evidence on currently available SNP panels does not permit meaningful assessment of analytic validity, the limited evidence on clinical validity is insufficient to conclude that SNP panels would perform adequately as a screening test and that there is no evidence available on the clinical utility of current panels.

 

Summary

Numerous studies have demonstrated the association of many gene panels and SNPs with prostate cancer.  These studies, in early stages of development, have generally shown a modest degree of association with future risk for prostate cancer. The clinical utility of these tests is uncertain; there is no evidence that information obtained from gene panels and SNP testing can be used to change management in ways that improve outcomes.

 

Summary of Evidence

The evidence for genetic and protein biomarker tests in individuals for assessment of prostate cancer risk and whom an initial prostate biopsy is being considered or for whom a rebiopsy is being considered includes systematic reviews and meta-analyses and primarily observational studies. Relevant outcomes are overall survival, disease-specific survival test accuracy, test validity, other test performance measures, resource utilization, hospitalizations, quality of life, treatment-related mortality, and treatment related morbidity. The evidence supporting clinical utility varies by test but has not been directly shown for any biomarker test. In general, comparison of biomarker test performance for predicting biopsy results with clinical examination performance including %fPSA are lacking. However, procedures for referrals for biopsy based on clinical examination vary making it difficult to quantify performance characteristics for this comparator. There is considerable variability in biopsy referral practices based on clinical examination alone and many of the biomarker tests do not have standardized cutoffs to recommend biopsy. Therefore, having prospective, comparative information on how the test results are expected to be used or actually being used in practice and the associated effects on outcomes will be needed to determine if the tests are improving net health outcomes. Many of the validation populations included men with positive DRE, PSA outside of the gray zone or older men for whom the information for the test is less likely to be informative. African-Americans have a high burden of morbidity and mortality but were not well represented in the study populations. It is not clear how to monitor geno typical men with low biomarker risk scores who continue to have symptoms or high/rising PSA. Comparison of the many biomarkers to one another is lacking and it is not clear how to use the tests in practice, particularly when the results contradict each other. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Practice Guidelines and Position Statements

American Urological Association (AUA)

In 2013, the American Urological Association (AUA) published guidelines for the early detection of prostate cancer:

In the U.S., early detection is driven by prostate specific antigen (PSA) – based screening followed by prostate biopsy for diagnostic confirmation.

While the benefits of PSA-based prostate cancer screening have been evaluated in randomized-controlled trials, the literature supporting the efficacy of DRE, PSA derivatives and isoforms (e.g. free PSA, 2proPSA, prostate health index, hK2, PSA velocity or PSA doubling time) and novel urinary markers and biomarkers (e.g. PCA3) for screening with the goal of reducing prostate cancer mortality  provide limited evidence to draw conclusions. While some data suggest use of these secondary screening tools may reduce unnecessary biopsies (i.e reduce harms) while maintain the ability to detect aggressive prostate cancer (i.e. maintain the benefits of PSA screening), more research is needed to confirm this. However, the likelihood of future population-level screening study using these secondary screening approaches is highly unlikely at least in the near future.       

 

Evaluation of Genomic Applications in Practice and Prevention (EGAPP)

In 2013, the Evaluation of Genomic Applications in Practice and Prevention Working Group published the following recommendations for PCA3 testing in prostate cancer, based on the Agency for Healthcare Quality and Research comparative effectiveness review:

  • Evidence was insufficient to recommend PCA3 testing to inform decisions for when to rebiopsy previously biopsy negative patients for prostate cancer, or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g. previous elevated PSA or suspicious digital rectal examination (DRE))
  • Evidence was insufficient to recommend PCA3 testing in men with cancer positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan.
  • The overall certainty of clinical validity to predict the diagnosis of prostate cancer using PCA3 is deemed “low.” Clinical use for diagnosis is discouraged unless further evidence supports improved clinical validity.
  • The overall certainty of net health benefit is deemed “low.” Clinical use is discouraged unless further evidence supports improved clinical outcomes.    

 

National Comprehensive Cancer Network (NCCN), Prostate Cancer Early Detection Version 2.2017   

Biomarker Testing: PSA Derivatives and other Tests

When the first recommendations for early detection programs for prostate cancer were made, serum tPSA was the only PSA-based test available. PSA derivatives and other assays exist that potentially improve the specificity of testing and thus may diminish the probability of unnecessary biopsies.

 

When a patient meets the standards for biopsy, sometimes the patient and physician wish to further define the probability of cancer before proceeding to biopsy with is associated risks. Several biomarker tests have been developed with the goals of refining patient selection for biopsies, decreasing unnecessary biopsies, and increasing the specificity of cancer detection, without missing a substantial number of higher grade (Gleason ≥ 7) cancers. These tests may be especially useful in men with PSA levels between 3 and 10 ng/mL. Most often, these tests have been used in patients who have had negative biopsy to determine if repeat biopsy is an appropriate consideration. 

 

The Panel recommends consideration of percent free PSA (%f PSA), 4Kscore, and Prostate Health Index (PHI) and 4Kscore, in patients with PSA levels > 3ng/mL who have not yet had a biopsy. %fPSA, PHI, 4Kscore, PCA3 and ConfirmMDx may also be considered for men who have had at least one prior negative biopsy and are thought to be a higher risk. 

 

Head-to-head comparisons have been performed in Europe for some of these tests, used independently or in combinations in the initial or repeat biopsy settings, but sample sizes were small and results varied. Therefore, the panel believes that no biomarker test can be recommended over any other at this time. Furthermore, a biomarker assay can be done alone or in addition to multiparametric MRI/refined biopsy techniques in the repeat biopsy setting. The optimal order of biomarker tests and imaging is unknown; and it remains unclear how to interpret results of multiple tests in individual patients – especially when results are contradictory. Results of any of these tests, when performed, should be included in discussions between clinician and patient to assist in decisions regarding whether to proceed with biopsy. 

 

PCA3

PCA3 is a noncoding, prostate tissue specific RNA that is over-expressed in prostate cancer. Current assays quantify PCA3 over-expression in post-DRE urine specimens. PCA3 appears most useful in determine which patients should undergo repeat biopsy.

 The FDA has approved the PCA3 assay to help decide, along with other factors, whether a repeat biopsy in men age 50 years or older with one or more previous negative prostate biopsies is necessary.

 

PHI

The PHI is a combination of the tPSA, fPSA and proPSA tests. The PHI was approved by the FDA in 2012 for use in those with serum PSA values between 4 and 10 ng/mL.

 

4KScore

The 4Kscore test is another combination test that measures free and tPSA, human kallikrein 2 (hK2), and intact PSA and also considers age, DRE results, and prior biopsy status. This test reports the percent likelihood of finding high grade (Gleason ≥ 7) cancer on biopsy.

 

The 4Kscore test is not FDA approved, instead it is considered a Laboratory Developed Test through one CLIA-accredited testing laboratory in Nashville, TN.

 

The panel consensus is that the test can be considered for patients prior to biopsy and for those with prior negative biopsy for men thought to be at higher risk for clinically significant prostate cancer. It is important for patients and their urologists to understand, however, that no cut-off threshold has been established for the 4Kscore. If a 4Kscore test is performed, the patient and his urologist should discuss the results to decide whether to proceed with a biopsy.   

 

ConfirmMDx

ConfirmMDx is a tissue based, multiplex epigenetic assay that aims to improve the stratification of men being considered for repeat prostate biopsy. Hypermethylation of the promotor regions of GSTP1, APC, and RASSF1 are assessed in core biopsy tissue samples. The test, performed in on CLIA-certified laboratory, is not FDA approved.

The panel believes that ConfirmMDx can be considered an option for men contemplating repeat biopsy because the assay may identify individuals at higher risk of prostate cancer diagnosis on repeat biopsy.

NCCN guideline does not include or indicate the use of APIFINY biomarker testing for prostate cancer risk assessment or management.

 

Prior Approval:

 

Not applicable

 

Policy:

See Related Medical Policy

  • 02.04.25 Prostate Specific Antigen Screening for Prostate Cancer
  • 02.04.57 Gene Expression Profiling and Protein Biomakers for Prostate Cancer Management

Genetic and Protein Biomarkers

Genetic and protein biomarkers for the diagnosis of prostate cancer are considered investigational. This includes, but is not limited to the following:

  • PCA3 testing
  • Kallikrein markers (e.g. 4Kscore™ Test)
  • Prostate Health Index (phi)/pro2PSA
  • APIFINY
  • ConfirmMDx
  • TMPRSS fusion genes
  • Gene hypermethylation (e.g. ConfirmMDx)
  • Metabolomic profiles (e.g. Prostarix™)
  • Mitochondrial DNA mutation testing (e.g. Prostate Core Mitomics Test™)
  • Candidate gene panels

The evidence for genetic and protein biomarker tests in individuals for assessment of prostate cancer risk and whom an initial prostate biopsy is being considered or for whom a rebiopsy is being considered includes systematic reviews and meta-analyses and primarily observational studies.  The evidence supporting clinical utility varies by test but has not been directly shown for any biomarker test. In general, comparison of biomarker test performance for predicting biopsy results with clinical examination performance including %fPSA are lacking. However, procedures for referrals for biopsy based on clinical examination vary making it difficult to quantify performance characteristics for this comparator. There is considerable variability in biopsy referral practices based on clinical examination alone and many of the biomarker tests do not have standardized cutoffs to recommend biopsy. Therefore, having prospective, comparative information on how the test results are expected to be used or actually being used in practice and the associated effects on outcomes will be needed to determine if the tests are improving net health outcomes. Many of the validation populations included men with positive DRE, PSA outside of the gray zone or older men for whom the information for the test is less likely to be informative. African-Americans have a high burden of morbidity and mortality but were not well represented in the study populations. It is not clear how to monitor geno typical men with low biomarker risk scores who continue to have symptoms or high/rising PSA. Comparison of the many biomarkers to one another is lacking and it is not clear how to use the tests in practice, particularly when the results contradict each other. The evidence is insufficient to determine the effects of this testing on net health outcomes and therefore, is considered investigational.

 

Single Nucleotide Polymorphisms Testing (SNPs)

  

Single nucleotide polymorphisms (SNPs) testing for cancer risk assessment of prostate cancer is considered investigational

 

Numerous studies have demonstrated the association of many gene panels and SNPs with prostate cancer.  These studies, in early stages of development, have generally shown a modest degree of association with future risk for prostate cancer. The clinical utility of these tests is uncertain; there is no evidence that information obtained from gene panels and SNP testing can be used to change management in ways that improve outcomes. Therefore, gene panels and SNP testing for cancer risk assessment of prostate cancer is considered investigational

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81229  Interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities
  • 81313  PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen] ratio (eg, prostate cancer)
  • 81479  Unlisted molecular pathology procedure
  • 81539  Oncology (high grade prostate cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein-2 [hK2], utilizing plasma or serum, prognostic algorithm reported as probability score (4Kscore Test)
  • 81551  Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy
  • 86316  Immunoassay for tumor antigen, other antigen, quantitative, (e.g. CA 50, 72-4. 549) each.  (PerA Coding and Reimbursement Committee this CPT should be used for the calculation of PHI value and immunoassay component pro2PSA)
  • 0005U Oncology (prostate) gene expression profile by real time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine algorithm reported as risk score
  • 0021U Oncology (prostate) detection of 8 autoantibodies (ARF 6, NKX3-1, 5-UTR-BMI1, CEP 164, 3-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score (APIFINY)

 

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  • Boegemann M, Stephan C, Cammann H, et al. The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged </=65 years. BJU Int. Jan 2016;117(1):72-79. PMID 25818705
  • Morote J, Celma A, Planas J, et al. Diagnostic accuracy of prostate health index to identify aggressive prostate cancer. An Institutional validation study. Actas Urol Esp. Jul-Aug 2016;40(6):378-385. PMID 26923032
  • Sreekumar A, Poisson LM, Rajendiran TM, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. Feb 12 2009;457(7231):910-914. PMID 19212411
  • Khan AP, Rajendiran TM, Ateeq B, et al. The role of sarcosine metabolism in prostate cancer progression. Neoplasia. May 2013;15(5):491-501. PMID 23633921
  • Cui Y, Cao W, Li Q, et al. Evaluation of prostate cancer antigen 3 for detecting prostate cancer: a systematic review and meta-analysis. Sci Rep. 2016;6:25776. PMID 27161545
  • Rubio-Briones J, Borque A, Esteban LM, et al. Optimizing the clinical utility of PCA3 to diagnose prostate cancer in initial prostate biopsy. BMC Cancer. 2015;15:633. PMID 26362197
  • Merdan S, Tomlins SA, Barnett CL, et al. Assessment of long-term outcomes associated with urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion at repeat biopsy. Cancer. Nov 15 2015;121(22):4071-4079. PMID 26280815
  • Van Neste L, Partin AW, Stewart GD, et al. Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. Prostate. Sep 2016;76(12):1078-1087. PMID 27121847
  • Leyten GH, Hessels D, Smit FP, et al. Identification of a candidate gene panel for the early diagnosis of prostate cancer. Clin Cancer Res. Jul 1 2015;21(13):3061-3070. PMID 25788493
  • Xiao K, Guo J, Zhang X, et al. Use of two gene panels for prostate cancer diagnosis and patient risk stratification. Tumour Biol. Aug 2016;37(8):10115-10122. PMID 26820133
  • Wang X, Yu J, Sreekumar A, et. al Autoantibody signatures in prostate cancer. N Engl J Med 2005;353:1224-35
  • Schipper M, Wang G, Giles N, et. al. Novel prostate cancer biomarkers derived from autoantibody signatures. Translation Oncology Volume 8, Number 2 April 2015 106-111   
  • APIFINY Armune Biosciences.

 

Policy History:

  • October 2017 - Interim Review, Policy Revised
  • June 2017 - Annual Review, Policy Revised
  • June 2016 - Policy revised and new policy created

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.